Type 2 Diabetes and Bone Health in Youth

项目摘要 2型糖尿病（T2D）与成人骨质量降低和骨折风险增加有关。但 尚不清楚早发性T2D是否对骨增量和强度有不良影响。平均诊断年龄 青年发病的T2D是在青春期中期，可能受到青春期胰岛素抵抗的影响，在肥胖的青年风险 治疗疾病鉴于骨矿物质积累发生在青少年时期，重要的是要了解 早发性糖尿病是否会干扰足够的骨矿物质积累，以及决定因素。 必须解决这一知识差距，以便我们能够采取干预措施，防止和扭转 潜在的风险因素，特别是儿童时期不良的骨骼健康可能会导致 骨质疏松症和骨折。该提案的总体目标是改善骨骼健康， 孩子本申请的中心目的是确定青年发病T2D对骨增长的影响， 微观结构和强度，并了解可能导致这些青年骨脆性的因素。我们 假设青年T2D患者高血糖症对骨形成有负面影响， 骨转换率低，骨生成和微结构改变。 为了验证这一假设，我们建议评估体积骨密度，微结构和强度 通过有限元导出的参数（失效载荷和刚度）使用高分辨率周边定量 在T2D青年患者中， 同样肥胖的青年与正常的体重控制。我们还将测量骨矿物质含量 (BMC)采用双能X线骨密度仪（DXA）测定骨密度（aBMD）。我们将联合收割机 这些评估包括通过DXA对身体成分进行仔细的代谢表型分析，胰岛素敏感性和 口服葡萄糖耐量试验（口服葡萄糖耐量试验，HbA1c）和肠道激素可能介导糖尿病对 骨头我们将解释骨骼健康的重要调节因素，包括种族、性别、青春期阶段， 体力活动（通过加速度计）和营养状况。 该研究在阐明高血糖对骨生成和微观结构的影响方面具有创新性 使用HRpQCT在青少年时期纵向观察，同时仔细考虑糖尿病相关因素 （糖尿病病程、治疗）和其他重要协变量。我们预计，我们将确定， 青年T2D患者的高血糖症对骨转换有不良影响，导致骨累积降低， T2D青年与体重正常和正常体重对照的同等肥胖青年相比， 我们从R21试点和可行性实验研究中获得的数据将为1）研究生活方式铺平道路 干预措施，目标是改善青春期骨生长，和2）评估的影响， 药物治疗对青年糖尿病患者骨骼健康的影响，为这些青年的临床管理提供最佳信息。

Project Summary Type 2 diabetes (T2D) is associated with lower bone quality and increased risk of fracture in adults. However, it is not known if early onset T2D has adverse effects on bone accrual and strength. The mean age of diagnosis of youth onset T2D is in mid-adolescence, likely influenced by pubertal insulin resistance in obese youth at risk for the disease. Given that bone mineral accrual is occurring in the adolescent years, it is important to understand whether early onset diabetes may be interfering with adequate bone mineral accrual, and the determining factors. It is imperative to address this knowledge gap so that we can institute interventions to prevent and reverse the underlying risk factors, particularly that adverse bone health in childhood may translate to increased risk for osteoporosis and fractures in adult life. The overarching goal of this proposal is to improve bone health in children. The central objective of this application is to determine the effect of youth onset T2D on bone accrual, microstructure and strength, and to understand the factors that may lead to bone fragility in these youth. We hypothesize that hyperglycemia in youth with T2D has a negative effect on bone formation and is associated with low bone turnover, altered bone accrual and microarchitecture. To test this hypothesis, we propose to evaluate volumetric bone mineral density, microarchitecture and strength by finite-element derived parameters (failure load and stiffness) using high resolution peripheral quantitative computed tomography (HRpQCT), and bone turnover markers longitudinally in youth with T2D compared with equally obese youth with normoglycemia and normal weight controls. We will also measure bone mineral content (BMC) and areal bone mineral density (aBMD) using dual energy X-ray absorptiometry (DXA). We will combine these evaluations with careful metabolic phenotyping of body composition by DXA, insulin sensitivity and glycemia (oral glucose tolerance test, HbA1c) and gut hormones that may mediate the effect of diabetes on bone. We will account for the important modulators of bone health including race-ethnicity, sex, pubertal stage, physical activity (by accelerometry), and nutrition status. The study is innovative in elucidating the effects of hyperglycemia on bone accrual and microstructure longitudinally in the adolescent years using HRpQCT, while carefully considering diabetes related factors (diabetes duration, treatment) and other important covariates. We anticipate that we will establish that hyperglycemia in youth with T2D has an adverse impact on bone turnover resulting in lower bone accrual and strength in youth with T2D compared with equally obese youth with normoglycemia and normal weight controls. Our data from this R21 pilot and feasibility experimental study will pave the way for 1) studying lifestyle interventions that target glycemia to improve bone accretion in adolescence, and 2) evaluation the effects of pharmacotherapy on bone health in youth with diabetes to best inform clinical management of these youth.